New Treatment Guidelines

New clinical practice guidelines for the diagnosis of tuberculosis disease and latent tuberculosis infection in adults and children have been prepared by a task force supported by the ATS, CDC, and IDSA (Clin Infect Dis 2016 Dec 8 [Epub ahead of print]). The guidelines are available for download on the IDSA website.

Practice Pearls

Drug-induced photosensitivity is a general term referring to cutaneous disease that results from the interaction of a chemical agent and sunlight. There are two types, phototoxicity (inflammatory) and photoallergy (immunologic). Clinically distinguishing between the two can be difficult; diagnostic tools such as phototesting and photopatch testing may be useful. Here is how the two reactions compare:

Phototoxicity

Photoallergy

Frequency

More common

Less common

Typical presentation

Exaggerated sunburn

Pruritic, eczematous eruption

Location

Sun-exposed skin

Sun-exposed skin and beyond

Prior sensitization required

No

Yes

Onset after initial exposure

Minutes to hours

>24 hours

Mechanism

Direct tissue injury

T-cell mediated hypersensitivity

Dose dependence

Yes

No

The essential characteristic of a photosensitizing drug is its ability to absorb ultraviolet (UV) and/or visible electromagnetic radiation. The wavelength of UV (<400 nm) is shorter than visible light. UVA (black light) is 320-400 nm; UVB (the sunburn region) is 280-320 nm; UVC (germicidal) is 200-280 nm. UVA, which penetrates skin deeply, does not damage directly DNA but is capable of generating highly reactive radicals that do have that ability. UVB is capable of directly damaging DNA, as is UVC. UVC is the highest energy and most dangerous type of UV radiation. Most photosensitivity reactions are caused by UVA.

The typical photosensitizing drug is of low molecular weight (200-500 dalton) with a planar, tricyclic, or polycyclic chemical configuration; it often has heteroatoms in its structure. Photoactivation results in generation of free radicals and singlet oxygen species. More than 300 drugs (mainly antimicrobials, NSAIDs, and cardiovascular agents) have been characterized as photosensitizers. A photosensitivity reaction generally resolves with drug discontinuation and sun avoidance, although patients who are unable to stop the offending drug will require topical steroids and protective physical measures to lessen symptoms. The Sanford Guide maintains a list* of possible and probable antimicrobial offenders (Clin Dermatol 34:571, 2016).

Many of us were taught that administration of ampicillin* or amoxicillin* results in a pruritic, maculopapular rash in most patients (65-100%) with infectious mononucleosis* (IM), a viral disease primarily caused by Epstein-Barr virus (EBV). This belief dates back to the 1960s. However, newer data suggest that the likelihood of rash may be considerably lower. An extensive literature search of all English language case reports and relevant articles addressing antibiotic-induced rash published from 1964 through June 2016 was recently conducted. Seventeen case reports and six retrospective studies were identified. The most commonly implicated drugs were amoxicillin, ampicillin, and azithromycin*. In the two most recent studies (published in 2013) the rate of rash was only 15% and 33%. The explanation for the higher rates reported in earlier publications is not known, but there are theories; for instance, impurities known to be present in early antibiotic preparations may have played a role, although not all published data support this suggestion. There seem to be two groups of patients with IM who experience an antibiotic-induced rash: a predominant group in whom the rash is likely due to transient and reversible EBV-mediated loss of immune tolerance (not a true penicillin allergy), and a smaller group of patients who appear to develop a true, persistent antibiotic hypersensitivity. The issue is not settled. For now, one can reasonably conclude that while the likelihood of antibiotic-induced rash in patients with IM is probably lower than 65-100%, we do not know with certainty what the actual rate of rash is, nor what the precise pathophysiologic mechanism is (Ann Pharmacother 2016 Sep 12 [Epub ahead of print]).

Nicolau syndrome, first described in the 1920s, is a rare complication of an intramuscular (IM) injection that results in varying degrees of necrosis involving the skin and adipose tissue. Offending drugs include penicillins*, local anesthetics, steroids, and NSAIDs. Nicolau syndrome is more prevalent in children, especially those under three years of age. Patients typically experience intense pain at the injection site immediately after the injection (minutes to a few hours), followed by bluish discoloration of the skin with possible ulceration and necrosis. Ulcers usually heal in a few months with scarring, and there may be transient neurological complications. The pathogenesis of Nicolau syndrome is not well understood; possible explanations include sympathetic nerve stimulation, direct vascular damage, perivascular inflammation, and vasospasm. Obese patients are at increased risk because the needle tip may not reach the muscle due to the thickness of the fat layer, resulting in drug injected outside of the muscle (sometimes repeatedly). There is no specific treatment for Nicolau syndrome. Conservative measures including debridement, topical corticosteroids, and analgesics are generally effective; vasoactive agents such as pentoxifylline may be helpful, and surgery is occasionally required. Three cases of Nicolau syndrome in children (ages 2, 2 and 9) following IM injection of benzathine penicillin G were recently reported. Two of the patients were fully recovered within one month; the third was significantly improved at two months follow-up (J Family Community Med 19:52, 2012; Bosn J Basic Med Sci 15:57, 2015;Case Rep Infect Dis 2016 Nov 1 [Epub ahead of print]).

Drug Shortages (US)

Antimicrobial drugs or vaccines in reduced supply due to increased demand, manufacturing delays, product discontinuation by a specific manufacturer, or unspecified reasons:

The Sanford Guide Web Edition was recently updated to a new platform in order to better serve our users. In addition to a clean new theme, the new site also enables us to add new features and functionality for all of our Web Edition and All Access subscribers.

The first change that users will notice is that content will no longer be updated on a monthly basis, but will instead be updated continually. This means that as soon as content is edited and reviewed by our editorial board, users will have access to the new information, bringing the latest changes in best practices to our users in real time. As always, our content will remain peer-reviewed by leaders in the field of infectious disease, and will reflect the best available guidance from the literature.

Our monthly ID Update newsletter, available on the Web Edition site, the Sanford Guide News site, and through e-mail subscription, will now be published earlier in the month. Updates to our mobile app content will be released according to this new schedule as well.

New Drug Approval

Tenofovir alafenamide (Vemlidy)* has been approved by the FDA for the treatment of chronic hepatitis B in adults with compensated liver disease. The recommended dosage is 25 mg orally once daily with food. Product availability: 25 mg tablets.

New Dosage Form Approval

The FDA has approved Maraviroc* (Selzentry) 20 mg/mL oral solution, 25 mg tablets, and 75 mg tablets. The prescribing information has been updated to include use in pediatric patients 2 years of age and older and weighing at least 10 kg.

New Treatment Guidelines

New clinical practice guidelines for the management of leishmaniasis have been prepared by a panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). The guidelines are available for download on the IDSA website.

Practice Pearls

Candida auris, an emerging fungus capable of invasive infection, is associated with high mortality and possible resistance to multiple antifungal drugs. It was first isolated in 2009 from the external ear canal of an inpatient in a Japanese hospital and has since been reported in a number of countries. A recent report describes the first seven US cases of C. auris infection reported to CDC as of August 31.C. auris is a serious concern because accurate laboratory identification requires specialized methods, it tends to be resistant to two or even three antifungal drug classes (azoles, echinocandins, polyenes), and it has caused outbreaks in health care settings. The optimal treatment regimen is not known (MMWR 65:1234, 2016).

Drug interactions that result in prolongation of the QT interval (QT-DDI) are often discovered many years after the drugs are marketed, suggesting the need for a more efficient strategy. A group of investigators recently mined the FDA Adverse Event Reporting System (FAERS) for signals indicating a QT-DDI. They then combined those data with ECGs from their institutional electronic health records (EHR). An unexpected interaction between lansoprazole (a proton-pump inhibitor) and ceftriaxone* was identified. Mean prolongation of the QTc (corrected QT interval) was 12 ms in males and 9 ms in females; men taking the combination were 1.4 times as likely to have a QTc above 500 ms as men taking a single drug. The largest effects were observed in white males and black females. The investigators then used patch-clamp electrophysiology to show that, in combination, the drugs block the hERG channel (the main mechanism by which drugs prolong the QT interval). As a negative control, no evidence of a QT-DDI was identified in the FAERS or EHR data, or in the electrophysiologic experiments, for the combination of lansoprazole and cefuroxime*. Further class analysis found no evidence in the FAERS or EHR for an interaction between any other cephalosporin and proton-pump inhibitor. The mechanism for this intriguing drug interaction, identified using a novel approach of data mining followed by laboratory experimentation, is not known (J Am Coll Cardiol 68:1756, 2016).

Many clinical trials have evaluated the use of cranberry products for UTI prevention, with inconsistent results (often negative, or positive results with flawed methodology). A recent report in JAMA describes a well-designed randomized, double-blind, placebo-controlled trial in elderly female nursing home residents intended to evaluate the effect of cranberry capsules on clinical and microbiologic outcomes. Study participants were administered two oral cranberry capsules (each capsule containing 36 mg of the active ingredient proanthocyanidin) or placebo once a day for a year. There was no significant difference in the primary outcome of bacteriuria plus pyuria, and also no significant differences in any of the secondary outcomes of the study such as symptomatic UTI, rates of death, or hospitalizations. The results of this study are consistent with the view that cranberry products cannot, at this time, be recommended for UTI prevention on the basis of proven benefit (JAMA 316:1879, 2016).

Vancomycin*-induced thrombocytopenia, first described in 1985, is uncommon, poorly characterized, and probably under-diagnosed. The mechanism appears to involve vancomycin-dependent, platelet-reactive antibodies (N Engl J Med 356:904, 2007). A group of researchers conducted a systematic search of the English-language literature using the PubMed, Scopus, and Web of Science databases; 29 case reports, five observational studies, two clinical trials, two letters, and one case series were identified for analysis and the results were recently published. In summary, the precise incidence of vancomycin-induced thrombocytopenia remains unclear. The reaction appears to be duration-dependent with a mean time to platelet nadir of eight days after the first exposure (and significantly shorter in cases of re-exposure). Nadir platelet counts ranged from 2,000 to 100,000 in patients who experienced bleeding. In the case reports, vancomycin-specific antibodies were detected in 13 of 17 patients who were tested. No conclusive association between vancomycin serum concentration and thrombocytopenia was observed. The platelet count returned to normal in a mean time of 5-6 days following discontinuation of vancomycin. Platelet transfusions were used in some patients with variable results; other measures such as corticosteroids, intravenous immunoglobulin, or rituximab were employed in a few patients with unclear benefit (Drug Safety 2016 Nov 15 [Epub ahead of print]).

Drug Shortages (US)

Antimicrobial drugs or vaccines in reduced supply due to increased demand, manufacturing delays, product discontinuation by a specific manufacturer, or unspecified reasons:

The Sanford Guide to HIV/AIDS Therapy 2016-2017 print guides are now available! The 24th edition of our Guide to HIV/AIDS Therapy provides practical clinical guidance for the treatment of HIV and AIDS, based on the latest available evidence. Popular with physicians, pharmacists, physician assistants, nurse practitioners, and other clinicians, the Sanford Guide to HIV/AIDS Therapy provides information that is convenient, concise, and reliable.

Featuring numerous updates, including the latest generation of combination formulations of ARV drugs and new formulations containing tenofovir alafenamide (TAF), the guide is available in both pocket-size and larger print “library” editions. Sections on differential diagnosis of HIV/AIDS-related clinical syndromes and opportunistic infections, immune reconstitution and treatment of specific OIs have been refined and updated to reflect current trends.

The Sanford Guide is excited to announce the release of its newest mobile app, Lederman’s Internal Medicine & Critical Care! Based on the upcoming sixth edition of Lederman’s classic pocketguide, the mobile app features guidance in the treatment of numerous internal medicine scenarios. Developed for use on iPhones, iPads, and Android mobile devices, the app includes the full text of the soon-to-be-released pocketguide, three dozen calculators, bookmarks with user-customized notes, and links to hundreds of external references.